Necroptosis

Necroptosis is a programmed form of necrosis, or inflammatory cell death. Conventionally, necrosis is associated with unprogrammed cell death resulting from cellular damage or infiltration by pathogens, in contrast to orderly, programmed cell death via apoptosis. The discovery of necroptosis showed that cells can execute necrosis in a programmed fashion and that apoptosis is not always preferable to necrotic cell death. Furthermore, the immunogenic nature of necroptosis favors its use in certain circumstances, such as aiding targeting of pathogens by the immune system. Necroptosis is well defined as a viral defense mechanism, allowing the cell to undergo “cellular suicide” in a caspase-independent fashion in the presence of viral caspase inhibitors. In addition to being a response to disease, necroptosis has also been characterized as a component of inflammatory diseases such as Crohn’s disease, pancreatitis, and myocardial infarction.

The signaling pathway responsible for carrying out necroptosis is generally understood. Production of TNFα during viral infection leads to stimulation of its receptor TNFR1. The TNFR-associated death protein TRADD signals to RIPK1 which recruits RIPK3 forming the necrosome. Phosphorylation of MLKL by the Ripoptosome drives oligomerization of MLKL, allowing MLKL to insert into and permeabilize plasma membranes and organelles. Integration of MLKL leads to the inflammatory phenotype and release of damage-associated molecular patterns (DAMPs), which elicit immune responses.

Necroptosis is specific to vertebrates and may have originated as an additional defense to pathogens. Necroptosis also acts as an alternative “fail-safe” cell death pathway in cases where cells are unable to undergo apoptosis, such as during viral infection in which apoptosis signaling proteins are blocked by the virus.

Cell suicide is an effective means of stemming the spread of a pathogen throughout an organism. In apoptotic responses to infection, the contents of an infected cell (including the pathogen) are contained and engulfed by phagocytosis. Some pathogens, such as human cytomegalovirus, express caspase inhibitors that arrest the apoptotic machinery of the host cell. The caspase-independence of necroptosis allows the cell to bypass caspase activation, decreasing the time during which the pathogen can inhabit the cell.

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